Phenotypic and genotypic diversity in Neisseria gonorrhoeae: Using population biology to understand antimicrobial resistance and pathogenesis

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The global spread of antibiotic resistance is a significant and increasing threat to global human health.Amongst increasing threats is the sexually transmitted disease gonorrhoea, for which last resorttreatment failures (i.e. third generation cephalosporins) have been reported in numerous countries.The WHO has highlighted that gonorrhoea may soon become untreatable as no vaccine or new drugsare currently available. The population structure of the causative pathogen Neisseria gonorrhoeae iscomplex and non-clonal due to the high level of genetic recombination that occurs between isolates.Prolific genetic recombination can confound population studies on gonococci, especially as suchstudies often focus on limited gene numbers such as Multi-locus sequence typing (MLST). Geneticplasticity allows gonococci to quickly generate a range of phenotypes though gene phasing andrecombination, the fittest of which can be selected for in vivo, facilitating rapid adaptation within thedifferent mucosal niches infected by these bacteria. This PhD aims to profile the antibiotic resistanceof gonococcal isolates from distinct mucosal sites and study the genomic and virulence relatedphenotype of these isolates. Linkage of these traits to the dynamics of infection transmission will beexamined through mathematical modelling. The successful candidate will determine the presence ofkey virulence factors by distinct immunoassays and proteomic, and infect cell lines representative ofthe male and female mucosal surfaces mimicking in vivo culture conditions with a diverse range ofclinical isolates of Ng. Minimal inhibitory concentrations (MICs) for clinically relevant antibiotics willbe assayed. For each isolate selection the genome will be sequenced plus any associated plasmididentified. Finally, data for MIC, virulence factor presence genomic diversity and cell line infectivitywill inform mathematical models to investigate potential evolutionary mechanisms of action.The outcomes are of translational importance: we will improve understanding of in vivo selection inrelation to antimicrobial susceptibility and virulence. In addition, we will identify if niche specificity isan important consideration for bacterial phenotypes that may then be utilised in using antimicrobials.Overall this project will provide multi-discipline training and improve our understanding of gonococcalpopulation biology.